Despite advances in supportive care, septic shock remains a major cause of morbidity and mortality. In 1995, there were an estimated more than 750,000 cases of sepsis in the United States, of whom 383,000 (51.1%) received intensive care and an additional 130,000 (17.3%) were ventilated in an intermediate care unit or cared for in a coronary care unit (Angus D C et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29:1303-10). Mortality was more than 28% or 215,000 annually. The incidence and mortality of sepsis increase with age. Sepsis is the second leading cause of death in among patients in non-coronary intensive care units and the 10th leading cause of death overall in the United States (Martin G S et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Eng J Med 2003; 348:1546-54). Furthermore, sepsis substantially reduces the quality of life of those who survive. Care of patients with sepsis costs an average of $22,000 per patient resulting in an economic burden of nearly $17 billion annually in the United States alone.
Sepsis generally develops as a result of the host response to infection. The pathogenesis of sepsis represents a complex constellation of interconnected events. Sepsis is a form of severe systemic inflammation due to local and systemic effects of circulating pro-inflammatory mediators. With the identification of the systemic inflammatory response as a major component in the pathogenesis of the septic shock syndrome, much of the recent work has focused on modulating this response. This includes anti-endotoxin therapies in patients with Gram-negative sepsis and therapies to modulate the pro-inflammatory mediators produced in response to infection, such as TNF-alpha, platelet-activating factor and complement. High-flow hemofiltration has the potential advantage of clearing both endotoxin and pro-inflammatory mediators. The bacterial toxins generated by the infecting organisms trigger complex immunologic reactions. A large number of mediators, including tumor necrosis factor, leukotrienes, lipoxygenase, histamine, bradykinin, serotonin and interleukin-2, have been implicated in addition to endotoxin (the lipid fraction of the lipopolysaccharides released from the cell wall of gram-negative enteric bacilli). Presently, the only recommended therapeutic approach remains close microbiological surveillance. Prophylactic antibiotics and enteral decontamination have only a minor role: they may have an adverse effect by the selection of multiple resistant strains. (Ronco C et al. A pilot study of coupled plasma filtration with adsorption in septic shock. Crit Care Med 2002; 30:1250-55).
The scientific literature provides some interesting experimental alternatives for treating sepsis. See for example J. A. Kellum and M. K. Dishart. Effect of Hemofiltration Filter Adsorption on Circulating IL-6 Levels in Spectic Rats. Critical Care 2002, 6:429-433 (hereinafter “Kellum”). Kellum discloses using a hydrogel-type membrane made from an acrylonitrile and sodium methallyl sulfonate copolymer to remove IL-6 from the blood of septic rats. Reduction in overall IL-6 levels was noted, however, the filter used has a limited absorption profile and not all sepsis-associated cytokines are removed.
However, many cytokines and other toxins are bound to the blood protein albumin. Conventional dialysis membranes do not remove substantial quantities of these protein-bound toxins from the blood because protein-impermeable membranes are generally used. Consequently, other extracorporeal circuits such as continuous renal replacement therapies (CRRT), coupled plasma filtration adsorption (CPFA) and continuous veno-venous hemodiafiltration (CVVHDF) may help minimize cell-associated cytokine concentrations in the blood of septic patents. See for example C. Tetta et al. Endotoxin and Cytokine Removal in Sepsis. Ther. Apher. 2002. 6:109-115. (hereinafter “Tetta”). Tetta concluded that CPFA may be preferable to CRRT and CVVHDF for treating septic patents, but that much clinical research was need to prove efficacy. These more invasive detoxification methods enable higher clearance of protein-bound toxins due to direct contact between the sorbent and the albumin/toxin-complex.
Continuous veno-venous hemofiltration (CVVH) was designed as a renal replacement therapy for patients with acute renal failure. In hemofiltration the blood is forced through a semipermeable membrane and water and small molecules are filtered out of the blood. Hemofiltration is slower and less physiologically disturbing than hemodialysis, it is often chosen over intermittent hemodialysis when blood pressure instability is a problem and CVVH is generally more efficient than peritoneal dialysis. In some intensive care units the use of CVVH is increasing as appreciation builds for its utility in the management of non-oliguric patients, in particular those with multiple organ dysfunction or failure, when their treatment includes very large amounts of intravenous fluids. And finally, experimental work is focusing on the possible role of CVVH as an adjunct in the treatment of the sepsis syndrome.
Healthy kidneys regulate the body's internal environment of water and salts and excrete the end products of the body's metabolic activities and excess water (urine). They also produce and release into the bloodstream hormones that regulate vital functions including blood pressure, red blood cell production, and calcium and phosphorus metabolism. Impaired kidney function may affect any or all of these processes and may be due to problems in the kidney, a disease in other organs, or caused by normal, age-related processes. It may be acute or chronic and either minor or life threatening. All of these distinctions are important determinants of prognosis and appropriate treatment. When a person's loss of kidney function is so severe as to be incompatible with life, the person is said to be in renal failure.
Acute Renal Failure (ARF) is a syndrome with multiple causes; its associated consequences affect all organ systems. Defined as a sudden loss of renal function (over several hours to several days), ARF results in derangements in extracellular fluid balance, acid base, electrolytes and divalent cation regulation. An increased serum creatinine concentration, accumulation of other nitrogen-based waste products, and often a decline in urinary output are the hallmarks of ARF.
Although many advances in organ support technologies have occurred during the past two decades, the absolute mortality rates for ARF acquired in the hospital and in the intensive care unit are approximately 45% and 70%, respectively (Thadhani R et al., Acute renal failure, N Engl J Med. 334:1448-60, 1996). However the demographics of ARF have changed, with patients generally being older and having a higher acuity of illness. Fortunately, renal function recovery (ability to discontinue dialysis) in the past 20 years has remained greater than 50-75% in survivors of ARF.
More than 20 definitions of ARF have been published to date. Despite the difficulty in defining the syndrome, ARF occurs in approximately 1% of hospitalized patients, in as many as 20% of patients treated in ICUs and as many as 4-15% of patients after cardiovascular surgery. Approximately 30% of patients who experience ARF will require renal replacement therapy (peritoneal dialysis, intermittent hemodialysis or continuous hemofiltration). Community-acquired ARF occurs in approximately 209 patients per one million population, and the frequency of this syndrome is increasing in hospitalized patients (Liano F et al., Epidemiology of acute renal failure: a prospective, multicenter, community-based study, Kidney Int. 50:811-8, 1996).
More than 50 identified pathophysiologic pathways are responsible for ARF. Traditionally, the evaluation of ARF has focused on the determination of whether the cause of renal failure is pre-renal (60% of community-acquired ARF, a condition resulting in decreased “effective renal perfusion”), post-renal (5-15% of community-acquired ARF, an obstruction to urinary outflow) or intrinsic renal (due to pathophysiologic derangements in the renal tubules, interstitium, vasculature or glomeruli; includes acute tubular necrosis, the most common cause of ARF in hospitalized patients) (Albright R C Jr. et al., Acute renal failure: a practical update, Mayo Clin Proc. 76:67-74, 2001).
Therapy to correct the pathophysiological impairments of ARF can be either nondialytic or dialytic in nature. Nondialytic therapy is focused on insuring that renal perfusion is maximized and correcting impairments. A variety of growth factors, hormones and drugs are currently under evaluation as nondialytic therapy for ARF. Dialytic therapy consists of peritoneal dialysis, intermittent hemodialysis or continuous hemofiltration.
Renal dialysis is an artificial method of maintaining the chemical balance of the blood when the kidneys have failed. The term dialysis refers to the process in which soluble waste products are separated from the blood using a semipermeable membrane. The blood is cleansed of impurities by cycling the blood through a machine containing a hemodialyzer membrane. On the other side of the membrane is a solution comprised of specific components that extract the impurities from the patient's blood. This solution is called the dialysate. Blood is both removed and returned to the patient via catheters. The effectiveness of dialysis depends on both its duration and efficiency.
Peritoneal dialysis, in contrast to hemodialysis, which cleanses the blood outside the body, works inside the body using the peritoneal membrane as the semipermeable barrier through which the blood can be filtered. The dialysate is infused directly into the patient's peritoneal cavity through a catheter; the cavity is used as a reservoir for the dialysate. Toxins in the blood filter through the peritoneal membrane into the cleansing solution, which is then withdrawn from the body through the same catheter and discarded. This procedure can be self-administered by patients several times a day.
Hemodialysis allows the extracorporeal removal of water and solutes from the blood by diffusion across a concentration gradient. Blood is pumped along one side of a semi-permeable membrane and a crystalloid solution is pumped in the opposite direction on the other side of the membrane. Solutes of very small molecular weight diffuse across the membrane in an attempt to equilibrate their concentrations. The pore size in the semi-permeable membrane determines its utility in ultrafiltration. Ultrafiltration membranes that are utilized in hemofilters allow the passage of molecules with a molecular weight of less than 20,000 Daltons. Thus ions and small chemicals present in plasma are filtered freely, including sodium, potassium, phosphate, bicarbonate, glucose and ammonia. So are larger soluble endogenous substances such as myoglobin, insulin, and interleukins, and certain exogenous substances circulating in plasma, including medications (vancomycin, heparin) and toxins (endotoxin, pesticides). Molecules that are bound to plasma proteins would not be filtered effectively by an ultrafiltration membrane.
Many side effects of hemodialysis are caused by rapid changes in the body's water and electrolyte balance during dialysis. These include muscle cramps, hypotension, complement activation and leukopenia. In addition patients undergoing peritoneal dialysis run the risk of serious peritoneal infections, some of which can progress to septic shock.
Extracorporeal circuits are well known in the prior art. However, the known extracorporeal circuits are used primarily as artificial kidneys and perfusion devices. Perfusion devices are primarily used to provide circulatory assistance after open heart surgery. Kidney diafiltration, dialysis and pure hemofiltration are processes used to replace the function of the failing or diseased kidney. These devices principally rely on semi-permeable membrane technology and the principles of osmotic diffusion to remove proteins, salts and urea from the blood. Additionally, kidney dialysis can be combined with ultrafiltration to remove excess fluid from the blood or be combined with substitution infusion fluid to replace fluids and salts lost in the hemodiafiltration process. However, extracorporeal circuits used to augment and/or replace diseased kidneys are not designed to remove the complex biological toxins the liver is responsible for.
U.S. Pat. No. 6,186,146 B1 (hereinafter “the '146 patent”) issued Feb. 13, 2001 to Glickman discloses an extracorporeal circuit having a filter device incorporated therein. Specifically, the '146 patent describes a treatment for cancer where cytotoxic drugs and biological agents are infused directly into a diseased organ. The patent's blood, leaving the treated organ, is diverted via an extracorporeal circuit wherein the cytotoxic and/or biological agent is removed from the blood via an inline filter before reaching the general circulation. No details as to the filter's composition are provided. However, the simple extracorporeal circuit disclosed in the '146 patent is intended to remove a defined concentration of a specific known chemotherapeutic and/or biological agent. It is not intended as a general replacement for a diseased organ. Moreover, no details are provided as to how one of ordinary skill in the art would use the disclosed device to remove other biological toxins.
Consequently, there remains a need for extracorporeal devices and methods that can be used to safely remove toxins from plasma in patients suffering from sepsis. Additionally, there remains a recognized need for extracorporeal devices and methods useful for removing toxins and balancing plasma water in patients with acute renal disease.